Podophyllotoxin is a naturally occurring podophyllum lignan isolated from the roots of the apple mandrake tree. In 1946, podophyllotoxin was found to function as an antimitotic by inhibiting microtubule formation. Shortly thereafter, this lignan was examined as a potential antitumor agent, but was found to exhibit prohibitive toxicity in Phase I cancer trials. More recently, podophyllotoxin has been proposed as a medicinal agent for the treatment of psoriasis, malaria and rheumatoid arthritis (U.S. Pat. No. 4,788,216 (1988).
In the 1960's, medicinal chemists at Sandoz developed several promising semisynthetic derivatives of podophyllotoxin. Two of these, etoposide (VP-16), and teniposide (VM-26), showed promise as antitumor agents and so were developed further. Clinical trials began in 1967 for teniposide, and in 1971 for etoposide. The latter drug has been extensively employed as a chemotherapeutic ever since. Etoposide appears to act by promoting topoisomerase II-mediated DNA strand scission. The appearance of etoposide resistance, both through alterations in topo II and through MDR, underscores the importance of developing fundamentally new types of analogues. Its side effects appear to limited to myelosuppression, which may be controlled by carefully regulating dosage.
Etoposide has displayed remarkable efficacy as a single agent in the treatment of small cell lung cancer, testicular cancer, several leukemias and Kaposi's sarcoma (the tumor most closely associated with AIDS). More recently, etoposide has been identified as a very good candidate for the treatment of life-threatening cytomegalovirus (CMV) infections. The spectrum of carcinomas for which etoposide is effective has been expanded notably in recent years through the practice of combination therapy. Thus, encouraging clinical reports have appeared relating the application of etoposide to the treatment of cancers of the cervix, ovary, breast and prostate, as well as advanced Hodgkin's disease.
The clinical success of etoposide has also resulted in efforts to develop etoposide analogues, particularly in recent years. However, probably due to the lag in enantioselective total synthetic efforts in the area, etoposide analogues bearing modified aglycon moieties have been lacking. Instead, most efforts have focused upon semisynthesis, especially variation of the carbohydrate sector (thioetoposide and NK-61 1) or prodrug synthesis (e.g. etopophos (BMY-40481)). K. -H. Lee has been particularly prolific in this regard, having published a long series of papers describing largely "northern hemisphere" modifications of the natural product. This continues to be an active research area.
The chemistry leading from (-)-podophyllotoxin to etoposide has been well worked out. However, the path from (.+-.)-podophyllotoxin to etoposide requires a tedious resolution step and is therefore not practical. Even so, most chemical syntheses of podophyllotoxin to date have led to racemic product.